α-Lipoic acid is one kind of coenzyme which is contained in the living body and acts on the glycolytic metabolism and the cycling through the TCA cycle, and is a substance in the form of yellow crystals having the structural formula C8H14O2S2, the molecular weight of 206.3, and the melting point of 60 to 62° C. α-Lipoic acid is also present in the human body, and is contained in many foods such as broccoli and red meat. Therefore, α-lipoic acid can be said to be a highly safe substance. In terms of function, α-lipoic acid is recognized as having strong antioxidant capacity in the living body thereby reducing oxidative stress, and as a chelating agent that is effective in the discharge of heavy metals. α-Lipoic acid is currently formulated into pharmaceutical products as “thioctic acid,” and thioctic acid preparations are usually sold as injections. As the efficacy and effect of the thioctic acid preparations, supplementation upon an increase in the demand of thioctic acid (at the time of vigorous physical labor), Leigh syndrome (subacute necrotic encephalomyelitis), and toxic (due to streptomycin or kanamycin) and noise-induced (occupational) inner ear hearing impairment are described in Drugs in Japan, Ethical Drugs (Non-Patent Document 1).
α-Lipoic acid had been approved for use in foods and cosmetics as a result of recent relaxation of regulations, and therefore, further applications thereof in these fields are expected.
α-Lipoic acid is in the form of a yellow powder, but since it is hardly soluble in water, its uses are limited. Furthermore, α-lipoic acid is very unstable to heat and light, and is difficult to be present stably in the preparation. Furthermore, it is a problem of α-lipoic acid that it has a characteristic sulfurous odor, and the odor becomes stronger when α-lipoic acid is degenerated and that it becomes gummy by heat. Thus, when α-lipoic acid is used in foods, cosmetics and pharmaceutical products, there is a serious problem in terms of the product quality and after-use feel.
In order to solve such problems as described above, Patent Document 1 suggests a water-soluble preparation containing α-lipoic acid or a pharmacologically acceptable salt thereof, and a sulfite or a hydrate thereof.
Patent Document 2 suggests a method for preparing a water-soluble preparation by dissolving α-lipoic acid in an organic solvent such as ethanol, subsequently adding an emulsifying agent and a polyhydric alcohol thereto, and bringing α-lipoic acid to an emulsified state by the physical action of an emulsifying machine or the like.
Furthermore, Patent Document 3 and Patent Document 4 suggest methods for preparing a water-soluble α-lipoic acid preparation, which methods enhance dispersibility in water and emulsification stability by mixing α-lipoic acid with an organic solvent such as ethanol, an emulsifying agent or a polyhydric alcohol.
However, the methods of bringing an emulsified state as described in these patent documents require a special apparatus called emulsifying machine, and when the particle size of the emulsification liquid is large, and when the distribution of the size of particle diameter is non-uniform, the emulsified state becomes easily separable. Furthermore, in other methods, it has been pointed out that since the dispersion of α-lipoic acid by emulsification is incomplete, the sulfurous odor characteristic to α-lipoic acid is strongly generated during storage.
Meanwhile, there are documents related to nanoparticle formation from retinoic acid. Patent Documents 5 to 8 disclose polyvalent metal inorganic salt-coated retinoic acid nanoparticles.
However, since retinoic acid is completely different from α-lipoic acid in structure, it would not be easily conceivable and had never been believed that α-lipoic acid is used instead of the retinoic acid of Patent Documents 5 to 8.
More detailed description will be given in this regard. First, as can be seen from the structures shown below, α-lipoic acid and retinoic acid have completely different structures except that they both contain one carboxyl group. Furthermore, α-lipoic acid is also completely different from retinoic acid in that α-lipoic acid contains sulfur atoms in the molecule and does not have any double bond. From the points as discussed above, it would not be easily conceivable to use α-lipoic acid instead of retinoic acid in the methods described in Patent Documents 5 to 8.
[Chem. 1] α-Lipoic Acid
Retinoic Acid
Secondly, retinoic acid is said to be an important in vivo hormone, which is, in the living body, involved with the growth and differentiation of cells, maintenance of homeostasis of the living body, morphogenesis, and the expression control of various genes by means of the binding to intranuclear retinoic acid receptors is proposed as a mechanism of action. On the other hand, as a coenzyme of the glycolytic system, α-lipoic acid catalyzes the oxidative decarbonation reaction from pyruvic acid to acetyl CoA, and thus is said to be an indispensable nutrient for cellular respiration and energy production. Furthermore, as a well-known function of α-lipoic acid, an antioxidant action is known. From the points as discussed above, retinoic acid and α-lipoic acid are completely different in terms of the functions in the living body and the expected pharmacological effects, and therefore, even from the viewpoint of the effectiveness demanded when its industrial application is believed, it would not be easily conceivable to use α-lipoic acid as a substitute for retinoic acid in the methods described in the Patent Documents 5 to 8.
Thirdly, it is reported in p. 410 of Non-Patent Document 2 that the pKa value of retinoic acid is 6.4, and it is described in the Discussion section on p. 411 that the pKa increases to 7 to 8 as retinoic acid forms micelles. On the other hand, Non-Patent Document 3 describes that the pKa value of α-lipoic acid is 4.76. From the points as described above, α-lipoic acid and retinoic acid are completely different in the properties related to dissociation. Therefore, it would not be easily conceivable to use α-lipoic acid as a substitute for retinoic acid in the methods described in Patent Documents 5 to 8.    Patent Document 1: Japanese Laid-open Patent Publication No. 2005-2096    Patent Document 2: Japanese Laid-open Patent Publication No. 2006-129841    Patent Document 3: Japanese Laid-open Patent Publication No. 2006-257010    Patent Document 4: Japanese Laid-open Patent Publication No. 2007-16000    Patent Document 5: Japanese Laid-open Patent Publication No. 2004-161739    Patent Document 6: International Publication No. 2005/037267 pamphlet    Patent Document 7: International Publication No. 2005/037268 pamphlet    Patent Document 8: International Publication No. 2005/070413 pamphlet    Non-Patent Document 1: Drugs in Japan, Ethical Drugs, Edition of 2007, Jiho, Inc., p. 1327 (2006)    Non-Patent Document 2: Robbert Creton, et al., Int. J. Dev. Biol., 39:409-414 (1995)    Non-Patent Document 3: Lester J. Reed, et al., JOURNAL OF THE AMERICAN CHEMICAL SOClETY, Vol. 75:1267 (1953)